Clinical trials in Alzheimer’s disease (AD) are under enormous pressure to produce results, as there have been no new successful AD drugs in recent years. A large multi-centre study published in Alzheimer’s Research & Therapy identifies an important issue in AD clinical trials; that participants that have been on acetylcholinesterase inhibitor (ChEI) treatment for mild AD may skew results when included in a study for a new drug.

Currently, the main treatment for mild-to-moderate AD is ChEIs, which include donepezil, rivastigmine and galantamine. These have been shown to have positive symptomatic effects on cognition and function and act by improving neuronal communication by preventing acetylcholine (ACh) degradation. Levels of ACh in the synaptic cleft of neurons is increased, which enhances cholinergic transmission and temporarily counteracts associated cognitive deficits.

In the past decade, research has been heavily focussed on finding ‘disease modifying drugs’ that will counteract the progression of AD by intervening in a specific part of the neuropathology. However, patients that are being included in these experimental drug studies are already being treated with ChEIs, due to the ethical problems of carrying out placebo-controlled clinical trials of more than 6 months in untreated individuals with AD.

This study aimed to observe the effects of long-term ChEI therapy in mild AD patients in a routine clinical setting. A cohort of 734 mild AD patients, taken from the Swedish Alzheimer Treatment Study (SATS), were assessed for cognition, global performance and functional capacity at the start of ChEI treatment (baseline), after 2 months, and semi-annually for a period of 3 years.

Corresponding author Carina Wattmo (Lund University, Sweden) explains: “Knowledge of longitudinal progression (cognitive, global and functional) in mild AD patients receiving current standard treatment, (ChEIs), is required for the evaluation of disease-modifying therapies. This is essential to compare the trajectories of those who have received a new therapy in addition to ChEI with those of patients treated only with ChEI, especially since therapies that may modify disease progression in AD require thorough long-term evaluation.”

The study found that long-term ChEI therapy may affect the rate of cognitive decline in different domains and therefore affect the comparison in cognitive tests between studies. The authors present novel mathematical prediction models to assess the long-term outcomes of new therapies added to ChEI treatment, which have use as a reference for future studies in mild AD. View the full study in Alzheimer’s Research & Therapy.

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